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elevated degrees of permeability and irregular diameter and incompletebasement membrane formations, that can contribute to abnormal nutrientand oxygen exchange, abnormal blood flow and elevated IFP. In tumors, the vascular endothelium is often poorly organized, leading toan increased permeability for macromolecules larger than 40 kDa,ultimately contributing to enhanced permeability and retention (EPR)effect, postulated as a positive regulator of nanotherapeutic accumulationat tumor sites. However, the degree of leakiness varies greatly betweendifferent tumor types. The combined effect of such heterogeneous systemsis an unpredictable perfusion of malignant tissues, which has crucialimplications for pathophysiology and therapeutic efficacy of nanotherapies,limiting uniform nanotherapeutic accumulation and penetration. Thedysregulated vascular and lymphatic networks of vessels that tend toaccompany some solid tumors can have an impact on nanotherapeuticdelivery.3.2. eCm Dysfunction and Diffusion GradientsThe ECM is a complex arrangement of proteins, glycosaminoglycans, andsignaling molecules that provides structural support and guidance tosurrounding tissues. Although ECM composition varies significantly acrosstumor types, tumor ECM generally tends to be denser than that of normaltissues. Some tumors, such as lymphomas and neuroblastomas, arerelatively stroma-poor, whereas others, like pancreatic cancers, exhibit adensely compact matrix. This dense supporting matrix results fromexcessive production and crosslinking of matrix components, driven by theirdesmoplastic nature. As is often observed in various cancers, compact ECMinhibits the penetration of large molecules. In fact, the tumor ECM oftenbecomes abnormally dense and stiff due to the excessive deposition ofcollagen, hyaluronic acid, and fibronectin, along with reduced degradationby matrix-modifying enzymes. This dense ECM serves as a physical barrier,limiting the penetration and diffusion of nanotherapeutics. In addition to acting as a physical barrier, the ECM can impede thedelivery of nanomedicines and macromolecular drugs by creating a highconcentration of target molecules, such as receptors on malignant cells,which leads to a phenomenon called the binding site barrier (BSB). TheBSB%u2019s significance was first recognized when antibodies were found toaccumulate predominantly in the perivascular region without penetratingdeeper into tumors. Furthermore, nanocarriers can bind to ECMcomponents, sequestering them and reducing their availability to reachtumor cells. Although saturation effects can overcome the barriers imposed110Potential of 3D tumor models for nanotherapies pre-clinical screeningVitor M. Gaspar1, Jo%u00e3o F. Mano, et al.